Process for preparing substituted 5-fluoro-1H-pyrazolopyridines

ABSTRACT

The present application relates to a novel and efficient process for preparing novel substituted 5-fluoro-1H-pyrazolopyridines of the formula (VI) 
                         
which are suitable as an intermediate for production of medicaments and for production of medicaments for treatment and/or prophylaxis of cardiovascular disorders. More particularly, the 5-fluoro-1H-pyrazolopyridines of the formula (VI) are suitable for preparation of the compound of the formula (I)
 
                         
which serves for production of medicaments, for production of medicaments for treatment and/or prophylaxis of cardiovascular disorders.

This application is a divisional application of U.S. application Ser.No. 14/796,703, filed Jul. 10, 2015, which is incorporated herein byreference, which is a divisional application of U.S. application Ser.No. 14/320,875, filed Jul. 1, 2014 (now U.S. Pat. No. 9,150,573), whichis incorporated herein by reference, which is a divisional applicationof U.S. application Ser. No. 13/684,670, filed Nov. 26, 2012 (now U.S.Pat. No. 8,802,847), which claims priority to European Application No.11192301.7, filed Dec. 7, 2011, and European Application No. 11190789.5,filed Nov. 25, 2011.

The present application relates to a novel and efficient process forpreparing novel substituted 5-fluoro-1H-pyrazolopyridines of the formula(VI)

which serve as an intermediate for production of medicaments and forproduction of medicaments for treatment and/or prophylaxis ofcardiovascular disorders.

More particularly, the 5-fluoro-1H-pyrazolopyridines of the formula (VI)are suitable for preparation of compound of the formula (I)

which serves for production of medicaments and for production ofmedicaments for treatment and/or prophylaxis of cardiovasculardisorders.

The compound of the formula (I) acts as a stimulator of solubleguanylate cyclase and can be used as an agent for prophylaxis and/ortreatment of cardiovascular disorders, for example for treatment ofhypertension and heart failure, stable and unstable angina pectoris,peripheral and cardiac vascular disorders, of arrthythmias, fortreatment of thromboembolic disorders and ischaemias such as myocardialinfarction, stroke, transitory and ischaemic attacks, peripheralperfusion disorders, prevention of restenoses such as after thrombosistherapy, percutaneous transluminal angioplasty (PTA), percutaneoustransluminal coronary angioplasty (PTCA), bypass, and for treatment ofarteriosclerosis, asthmatic disorders and diseases of the urogenitalsystem, for example prostate hypertrophy, erectile dysfunction, femalesexual dysfunction, osteoporosis, glaucoma, pulmonary hypertension,gastroparesis, scleroderma and incontinence.

The compound of the formula (I) may be present in various crystal formsand solvates. The compound of the formula (I) exists in five polymorphswith melting points 257° C. (polymorph I), 253° C. (polymorph II), 247°C. (polymorph III), 246° C. (polymorph IV), 234° C. (polymorph V), adimethylformamide/water solvate (DMF content 13.6%, water content 0.9%),a di-dimethyl sulphoxide solvate (stoichiometric value: 26.8% DMSO), atriacetic acid solvate (29.7% acetate), a monohydrate (4.1% water) and adihydrate (7.8% water). The prior art, WO 2011/147809, describes thecompound of the formula (I) in Example 1 as a substance.

The crystal polymorph of the compound of the formula (I) in polymorph(I) is notable for stability and particularly for the fact that it isstable even in the micronization process and thus no conversion andrecrystallization takes place.

The di-dimethyl sulphoxide solvate of the compound of the formula (I)has the advantage of much better filterability than the substance in theprior art. Furthermore, the preparation process via the di-dimethylsulphoxide solvate of the compound of the formula (I) leads to a veryhigh purity of the compound of the formula (I).

WO 03/095451, WO 2011/064156 and WO 2011/064171 disclose the synthesisof pyrazolopyridines unsubstituted on the pyridine ring. In thesedisclosures, the bicyclic ring system is built up by reaction ofphenylbenzyl hydrazine with ethyl cyanopyruvate. This synthesis methodis unsuitable for the formation of 5-fluoro-1H-pyrazolopyridines.

WO 2009/018415 describes the synthesis of5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-amine E. Selective dechlorinationof the nicotinic acid A to give the compound B, subsequent conversion tothe amide C, the reduction thereof to the nitrile and the finalcyclization with hydrazine hydrate form the5-fluoro-1H-pyrazolo[3,4-b]pyridine core. Scheme 1 below illustrates thesynthesis.

A disadvantage of this process is that, proceeding from5-fluoro-1H-pyrazolo[3,4-b]pyridine E, further steps such as thediazotization reaction and conversion to the iodo compound, followed byan alkylation with a benzyl derivative and subsequent functionalizationfor introduction of the cyano group are required in order to obtain thedesired 5-fluoro-1H-pyrazolopyridines of the formula (VI). This isillustrated by way of example in Scheme 2.

A further disadvantage is that the diazotization is conducted underanhydrous conditions and the diazonium salt has to be isolated, whichnecessitates considerable safety precautions on conversion to theindustrial scale and thus causes high production costs.

A further disadvantage is that the alkylation with a benzyl derivativeproceeds unselectively and the product is obtained in only a low yieldafter complex purification and separation of the isomers.

A further disadvantage is that, in the course of cyanation, toxic coppercyanide has to be handled, which necessitates additional safetyprecautions in the preparation and in the disposal of mother liquors andaqueous phases, and thus causes high production costs.

A further disadvantage is that the preparation of5-fluoro-1H-pyrazolopyridines of the formula (VI), according to theprocess described in Scheme 1, entails the preparation and purificationof seven intermediates and affords only a small overall yield.

It is an object of the present invention to provide an efficient processwith high yield for preparation of 5-fluoro-1H-pyrazolopyridines of theformula (VI)

as a key component for an efficient process with high yield forpreparation of compound of the formula (I)

and the N-oxides, salts, solvates, salts of N-oxides and solvates of theN-oxides and salts thereof.

This object is achieved in accordance with the present invention, asfollows. Scheme 3 below illustrates the individual reaction steps by wayof example.

Step a) is already known for the unsubstituted pyrazolopyridines through(WO 03/004503 (Example IIIb) and WO 03/095451 (Example 2A)):

Compared to the prior art (WO 03/004503, Example IIIb and WO 03/095451,Example 2A), the preparation of IV proceeds with a much higher yield.

A further advantage is that, rather than the corrosive trifluoroaceticacid, ethanol, which is much less expensive, is used as the solvent.

A further advantage is that the reaction time is considerably shortercompared to the prior art.

A further advantage is that the preparation of IV proceeds with highselectivity and the product is formed in high purity without significantby-product formation, and no complex purification procedures arerequired.

A further advantage is that IV is obtained by crystallization in highyield and purity.

Steps d)-g) are already known for the unsubstituted pyrazolopyridinesthrough WO 03/095451, WO 2011/064156 and WO 2011/064171 and can be usedanalogously.

Specifically, the process according to the invention for preparing acompound of the formula (VI)

comprises the cyclization of the 5-aminopyrazole derivative (IIa)

-   -   in which    -   T¹ is (C₁-C₄)-alkyl,        in the presence of a suitable acid with the aldehyde (III)

-   -   in which R¹ and R² are each independently methyl, ethyl,        isopropyl, phenyl or, together with the nitrogen atom to which        they are bonded, are

to give the ester of the formula (IVa)

in which T¹ is as defined above,the subsequent reaction thereof with ammonia or formamide to give theamide of the formula (V)

and the subsequent dehydration to give the nitrile (VI).

The present invention further provides for the use of the compound ofthe formula (VI)

for preparation of the compound of the formula (I)

and the N-oxides, salts, solvates, salts of N-oxides and solvates of theN-oxides and salts thereof.

The present invention further provides for the use of the compound ofthe formula (III)

-   -   in which R¹ and R² are each independently methyl, ethyl,        isopropyl, phenyl or, together with the nitrogen atom to which        they are bonded, are

for preparation of the compound of the formula (I)

and the N-oxides, salts, solvates, salts of N-oxides and solvates of theN-oxides and salts thereof.

The present invention further provides for the use of the compound ofthe formula (VI) for preparation of the compound of the formula (I) asspecified above, wherein the compound of the formula (VI) is convertedto the compound of the formula (VII)

-   -   the latter is subsequently reacted in an inert solvent in the        presence of a suitable base with the compound of the formula        (VIIIa)

-   -   to give the compound of the formula (VIII)

-   -   and then the latter is reduced in an inert solvent in the        presence of a suitable reducing agent to give the compound (IX)

-   -   then the latter is reacted in the presence of a suitable base in        the presence or absence of a solvent with methyl chloroformate        or with dimethyl dicarbonate to give the compound of the formula        (I)

and the resulting compound of the formula (I) is optionally convertedwith the appropriate (i) solvents and/or (ii) acids or bases to thesolvates, salts and/or solvates of the salts thereof.

The conversion (VI)→(VII) is effected by methods known to those skilledin the art in a two-stage process, first to form the imino ester withsodium methoxide in methanol at 0° C. to +40° C. and then nucleophilicaddition of one ammonia equivalent, for example ammonia or ammoniumchloride, in acetic acid or an alcohol to form the amidine (VII) at +50to +150° C.

Suitable alcohols for the conversion (VI)→(VII) are alcohols such asmethanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol.

Inert solvents for the process step (VII)+(VIIIa)→(VIII) are alcoholssuch as methanol, ethanol, n-propanol, isopropanol, n-butanol ortert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbonssuch as benzene, xylene, toluene, hexane, cyclohexane or mineral oilfractions, or other solvents such as dimethylformamide (DMF), dimethylsulphoxide (DMSO), sulpholane, N,N′-dimethylpropyleneurea (DMPU),N-methylpyrrolidone (NMP), pyridine, acetonitrile or else water. It islikewise possible to use mixtures of the solvents mentioned. Preferenceis given to DMF and sulpholane.

Suitable bases for the process step (VII)+(VIIIa)→(VIII) are alkalimetal hydroxides, for example lithium hydroxide, sodium hydroxide orpotassium hydroxide, alkali metal carbonates such as lithium carbonate,sodium carbonate, potassium carbonate or caesium carbonate, alkali metalhydrogencarbonates such as sodium hydrogencarbonate or potassiumhydrogencarbonate, alkali metal alkoxides such as sodium methoxide orpotassium methoxide, sodium ethoxide or potassium ethoxide or potassiumtert-butoxide, or organic amines such as triethylamine,diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Preference is given totriethylamine.

The reaction (VII)+(VIIIa)→(VIII) is generally conducted within atemperature range of +20° C. to +150° C., preferably at +80° C. to +120°C., optionally in a microwave. The conversion can be effected atstandard, elevated or reduced pressure (for example from 0.5 to 5 bar).In general, standard pressure is employed.

The compound of the formula (VIIIa) can be prepared analogously to theliterature L. F. Cavalieri, J. F. Tanker, A. Bendich, J. Am. Chem. Soc.,1949, 71, 533.

The reductions (VIII)→(IX) are effected in the presence of a suitablecatalyst in an inert solvent within a temperature range of +20° C. to+100° C. under hydrogen pressure (for example from 1 to 100 bar).Preference is given to a temperature range of 40° C. to 80° C. and ahydrogen pressure range of 5 to 70 bar.

Inert solvents for the reduction (VIII)→(IX) are, for example, alcoholssuch as methanol, ethanol, n-propanol, isopropanol, n-butanol ortert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, or othersolvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO),N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine,acetonitrile or else water. It is likewise possible to use mixtures ofthe solvents mentioned. Preference is given to DMF and pyridine.

Suitable catalysts for the conversion (VIII)→(IX) are, for example,palladium on activated carbon, platinum on carbon, palladium hydroxideor Raney nickel.

The reduction (VIII)→(IX) can alternatively be effected with a metal ormetal salt, for example iron, zinc or tin(II) chloride in a suitableacid, for example hydrogen chloride/hydrochloric acid, sulphuric acid,phosphoric acid or acetic acid, within a temperature range of +20° C. to+140° C.

Inert solvents for process step (IX)→(I) are, for example, alcohols suchas methanol, ethanol, n-propanol, isopropanol, n-butanol ortert-butanol, ethers such as diethyl ether, diisopropyl ether, dioxane,tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethylether, halogenated hydrocarbons such as dichloromethane,trichloromethane, carbon tetrachloride, trichloroethylene orchlorobenzene, hydrocarbons such as benzene, xylene, toluene, hexane,cyclohexane or mineral oil fractions, or other solvents such asdimethylformamide (DMF), dimethyl sulphoxide (DMSO),N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP),acetonitrile, ethyl acetate or else water. It is likewise possible touse mixtures of the solvents mentioned. Preference is given toisopropanol and tetrahydrofuran, and to a mixture of isopropanol andtetrahydrofuran.

Suitable bases for the process step (IX)→(I) are alkali metal hydridessuch as sodium hydride, alkali metal hydroxides, for example lithiumhydroxide, sodium hydroxide or potassium hydroxide, alkali metalcarbonates such as lithium carbonate, sodium carbonate, potassiumcarbonate or caesium carbonate, alkali metal hydrogencarbonates such assodium hydrogencarbonate or potassium hydrogencarbonate, alkali metalalkoxides such as sodium methoxide or potassium methoxide, sodiumethoxide or potassium ethoxide or potassium tert-butoxide, or organicamines such as triethylamine, diisopropylethylamine, pyridine,4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Preference is given totriethylamine.

The reaction (IX)→(I) is generally conducted within a temperature rangeof −10° C. to +70° C., preferably at 0° C. to +50° C. The conversion canbe effected at standard, elevated or reduced pressure (for example from0.5 to 5 bar). In general, standard pressure is employed.

Compounds of the formula (IIa) are known from the literature and can beprepared in analogy to Example 20A in WO 00/06569.

Compounds of the formula (III) are known from the literature H.Yamanaka, S. Yamashita and T. Ishihara, Synlett 353-354 (1993). Thesynthesis disclosed therein is illustrated in Scheme 4.

A disadvantage of this process is that, in the preparation of (XVIb),according to H. Yamanaka, M. Kuwabara, M. Okudo, K. Fukunishi and M.Nomura, Nippon Kagaku Kaishi (10) 1988-1994 (1985), only a yield of 66%is achieved and, in this process, very large amounts (2.79 kg per kg of(XVIb)) of by-product (dimethyldibenzyl nitrobenzenesulphonate) areobtained, which have to be removed and disposed of.

A further disadvantage of this process is that, according to H.Yamanaka, H. Ganbayashi, M. Kuwabara, K. Fukunishi and M. Nomura, NipponKagaku Kaishi (7) 1036-1043 (1988), proceeding from (XVIb), thealkylation requires 10 equivalents of the carcinogenic alkylating agentmethyl iodide.

A further disadvantage of this process is that, according to H.Yamanaka, S. Yamashita and T. Ishihara, Synlett 353-354 (1993), thereaction of O with morpholine forms not only the desired product (IIIb)but also 11% of the by-product (IIIa), which necessitates a complexpurification, the result being that the overall synthesis forpreparation of (IIIb) gives only a low overall yield and causes highproduction costs.

The synthesis described therein, however, is unsuitable for thepreparation of the aldehydes of the formula (III) on the industrialscale, and so a new and efficient synthesis has been developed, which isillustrated by way of example in Scheme 5.

The compound of the formula (XIII) is known according to the literatureMarkovskii, L. N.; Kolesnik, N. P.; Shermolovich, Yu. G Zhurnal ObshcheiKhimii (1980), 50(4), 826-829. The synthesis disclosed therein isillustrated in Scheme 6.

The synthesis described therein, however, for reasons including the lowyield, is unsuitable for the preparation of the aldehydes of the formula(III) on the industrial scale.

The present invention further provides a process for preparing compoundsof the formula (III)

-   -   in which R¹ and R² are each independently methyl, ethyl,        isopropyl, phenyl or, together with the nitrogen atom to which        they are bonded, are

wherein trifluoromethanesulphonic anhydride of the formula (X) isreacted with 2,2,3,3-tetrafluoro-1-propanol of the formula (XI) withoutsolvent and the resulting 2,2,3,3-tetrafluoropropyltrifluoromethanesulphonate of the formula (XII) is reacted with acompound of the formula (XIIa)

-   -   in which R¹ and R² are each as defined above        to give a compound of the formula (XIIIa)

-   -   in which R¹ and R² are each as defined above        and with methyl methanesulphonate to give a compound of the        formula (XIVa)

-   -   in which R¹ and R² are each as defined above        and with sodium hydroxide to give a compound of the formula        (XVa)

-   -   in which R¹ and R² are each as defined above        and finally converted under basic conditions to give the        compound of the formula (III).

The present invention further preferentially provides a process forpreparing compounds of the formula (IIIa)

wherein trifluoromethanesulphonic anhydride of the formula (X) isreacted with 2,2,3,3-tetrafluoro-1-propanol of the formula (XI) withoutsolvent and the resulting 2,2,3,3-tetrafluoropropyltrifluoromethanesulphonate of the formula (XII) is reacted withmorpholine to give a compound of the formula (XIII)

and with methyl methanesulphonate to give a compound of the formula(XIV)

and with sodium hydroxide to give a compound of the formula (XV)

and finally with addition of morpholine to give the compound of theformula (III).

The new synthesis has the advantage over the prior art that theintermediate (XII) and the intermediates (XIV) and (XV) unknown to dateneed not be isolated, which greatly reduces the industrial complexity ofthe synthesis.

The yields of the resulting aldehydes of the formula (III) are muchhigher with the new synthesis process than in the prior art.

“Basic conditions” in the context of the invention for the process step(XIVa) to (XVa) means that the acid formed in the reaction is scavengedby auxiliary bases, for example sodium hydroxide, potassium hydroxide,potassium carbonate, sodium carbonate, or triethylamine to form thecorresponding salts.

Compared to the prior art, the preparation of (XIII) proceeds with amuch higher yield. It is advantageous that no solvent is required forpreparation of (XII), and that the intermediate XII is used withoutfurther purification in the subsequent stage to give (XIII).

A further advantage of this process is that no significant wastes areformed in the preparation of (XIII). It is also advantageous that thetrifluoromethanesulphonic acid and morpholine can be recovered from themorpholinium trifluoromethanesulphonate formed.

Compared to the prior art, the preparation of (XIV) requires only oneequivalent of the alkylating agent. The reaction is conducted withoutsolvent and proceeds virtually quantitatively, which achieves a highspace-time yield.

A further advantage of this process is that the product (XIV) is notisolated, (XIV) is dissolved in water and this solution is reacted withsodium hydroxide solution to give (XV).

A further advantage of this process is that the product (XV) is also notisolated; reaction of the aqueous solution with morpholine affords(IIIa) as the sole product in high yield.

A further advantage of this process is that (IIIa) is obtained in highoverall yield and purity by crystallization.

The cyclization of the 5-aminopyrazole derivative of the compound (IIa)with the aldehyde of the compound (III) to give the compound of theformula (IV) is effected in an inert solvent, optionally in the presenceof an acid and optionally of an alkali metal salt, within a temperaturerange of +10° C. to +200° C., preferably at +20° C. to +100° C., atstandard pressure, within, for example 2 to 50 hours, preferably within2 to 20 hours.

Acids are, for example, hydrochloric acid, trifluoroacetic acid andmethanesulphonic acid. Preference is given to methanesulphonic acid andhydrochloric acid.

Alkali metal salts are sodium chloride or lithium chloride. A preferredalkali metal salt is lithium chloride.

Inert solvents are, for example, alcohols such as methanol, ethanol,n-propanol or iso-propanol, n-butanol, ethers such as diethyl ether,dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycoldimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane,cyclohexane or mineral oil fractions or other solvents, acetonitrile orN,N-dimethylformamide, or mixtures of solvents. Preference is given toethanol, diethylene glycol dimethyl ether or dioxane.

The preferred formation of the amide (IVa)→(V) is effected by reactionin an inert solvent with formamide in the presence of a base within atemperature range of 0° C. to +150° C., preferably of +20° C. to +130°C., at standard pressure or elevated pressure, within 2 to 24 hours.

Inert solvents are, for example, alcohols such as methanol, ethanol,n-propanol or iso-propanol. Preference is given to ethanol.

Suitable bases for the preferred process step (IVa)→(V) are alkali metalcarbonates such as lithium carbonate, sodium carbonate, potassiumcarbonate or caesium carbonate, alkali metal hydrogencarbonates such assodium hydrogencarbonate or potassium hydrogencarbonate, alkali metalalkoxides such as sodium methoxide or potassium methoxide, sodiumethoxide or potassium ethoxide or potassium tert-butoxide, or organicamines such as triethylamine, diisopropylethylamine, pyridine,1,8-diazabicyclo[5 4.0]undec-7-ene (DBU) or1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Preference is given to sodiummethoxide and sodium ethoxide.

The formation of the amide (IVa)→(V) is alternatively effected byreaction with ammonia within a temperature range of 0° C. to +50° C.,preferably of +20° C. to +30° C., at standard pressure or elevatedpressure, within 24 to 72 hours.

Inert solvents are, for example, alcohols such as methanol, ethanol,n-propanol or iso-propanol. Preference is given to using a solution ofammonia in methanol in a concentration of 5N to 7N.

The dehydration of the amide (V) to the nitrile (VI) is effected in aninert solvent, optionally in the presence of a suitable base, with asuitable dehydrating agent, for example phosphorus oxychloride,trifluoroacetic anhydride, acetic anhydride or trifluoromethanesulphonicanhydride, within a temperature range of 0° C. to +150° C., preferablyat +50° C. to +110° C., within 1 to 12 hours.

Preference is given to phosphorus oxychloride.

Inert solvents are ethers such as diethyl ether, dioxane,tetrahydrofuran (THF), glycol dimethyl ether or diethylene glycoldimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane,cyclohexane or mineral oil fractions or other solvents, pyridine,sulpholane, acetonitrile or N,N-dimethylformamide, or mixtures ofsolvents. Preference is given to sulpholane and acetonitrile.

Suitable bases are, for example, organic amines such as triethylamine,diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Preference is given topyridine.

The compounds described in the context of the process according to theinvention may also be in the form of the salts, solvates or solvates ofthe salts thereof.

The compounds described in the context of the process according to theinvention may, depending on the structure, also be in the form of thetautomers thereof.

Preferred salts in the context of the invention are physiologicallyacceptable salts of the compounds used and prepared in the processaccording to the invention.

Physiologically acceptable salts of the compounds used and prepared inthe process according to the invention include acid addition salts ofmineral acids, carboxylic acids and sulphonic acids, for example saltsof hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid,benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid,propionic acid, lactic acid, tartaric acid, malic acid, citric acid,fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds used and prepared inthe process according to the invention also include salts of customarybases, by way of example and with preference alkali metal salts (e.g.sodium and potassium salts), alkaline earth metal salts (e.g. calciumand magnesium salts) and ammonium salts derived from ammonia or organicamines having 1 to 16 carbon atoms, by way of example and withpreference ethylamine, diethylamine, triethylamine,ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine,dibenzylamine, N-methylmorpholine, dihydroabiethylamine, arginine,lysine, ethylenediamine and methylpiperidine.

In the context of the invention, solvates refer to those forms of thecompounds used and prepared in the process according to the inventionwhich, in the solid or liquid state, form a complex by coordination withsolvent molecules. Hydrates are a specific form of the solvates in whichthe coordination is with water.

In the context of the present invention, the substituents, unlessspecified otherwise, are each defined as follows:

Alkyl in the context of the invention is a linear or branched alkylradical having 1 to 4 carbon atoms. Preferred examples include: methyl,ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl andtert-butyl.

The present invention is illustrated in detail below by non-limitingpreferred examples and comparative examples. Unless stated otherwise,all amounts given refer to percentages by weight.

The present invention provides a process for preparing compounds of theformula (VI)

characterized in that the compound of the formula (V)

is prepared by reaction of an ester of the formula (IVa)

in whichT¹ is (C₁-C₄)-alkylwith formamide.

The present invention further provides a process as described above,characterized in that an ester of the formula (IVa) is prepared bycyclization of the 5-aminopyrazole derivative (IIa)

in whichT¹ is (C₁-C₄)-alkylin the presence of an acid and an alkali metal salt with an aldehyde ofthe formula (III)

in which R¹ and R² are each independently methyl, ethyl, isopropyl,phenyl or, together with the nitrogen atom to which they are bonded, are

The present invention further provides a process as described above,characterized in that the aldehyde used in the cyclization reaction isthe compound of the formula (IIIa)

The present invention further provides a process for preparing aldehydesof the formula (III)

in which R¹ and R² are each independently methyl, ethyl, isopropyl,phenyl or, together with the nitrogen atom to which they are bonded, are

characterized in that trifluoromethanesulphonic anhydride is reactedwith 2,2,3,3-tetrafluoro-1-propanol without solvent and the resulting2,2,3,3-tetrafluoropropyl trifluoromethanesulphonate is reacted with acompound of the formula (XIIa)

in which R¹ and R² are each as defined above, to give a compound of theformula (XIIIa)

in which R¹ and R² are each as defined aboveand with methyl methanesulphonate to give a compound of the formula(XIVa)

in which R¹ and R² are each as defined aboveand with sodium hydroxide to give a compound of the formula (XVa)

in which R¹ and R² are each as defined aboveand finally converted under basic conditions to give the compound of theformula (III).

The present invention further provides a process for preparing compoundsof the formula (IIIa)

wherein trifluoromethanesulphonic anhydride of the formula (X) isreacted with 2,2,3,3-tetrafluoro-1-propanol of the formula (XI) withoutsolvent and the resulting 2,2,3,3-tetrafluoropropyltrifluoromethanesulphonate of the formula (XII) is reacted withmorpholine to give a compound of the formula (XIII)

and with methyl methanesulphonate to give a compound of the formula(XIV)

and with sodium hydroxide to give a compound of the formula (XV)

and finally with addition of morpholine to give the compound of theformula (IIIa).

The present invention further provides a process for preparing thecompound of the formula (I)

characterized in that compounds of the formula (VI)

are used,these being characterized in that they are prepared by the processspecified above and the resulting compounds of the formula (I) areoptionally converted with the appropriate (i) solvents and/or (ii) acidsor bases to the solvates, salts and/or solvates of the salts thereof.

The present invention further provides a process for preparing thecompound of the formula (I), characterized in that compounds of theformula (VI)

are used,these being characterized in that they are prepared by the processesspecified above and the resulting compounds of the formula (I) areoptionally converted with the appropriate (i) solvents and/or (ii) acidsor bases to the solvates, salts and/or solvates of the salts thereof.

The present invention further provides a process for preparing thecompound of the formula (I), characterized in that compounds of theformula (VI)

are used,these being characterized in that they are prepared by the processesspecified above and the resulting compounds of the formula (I) areoptionally converted with the appropriate (i) solvents and/or (ii) acidsor bases to the solvates, salts and/or solvates of the salts thereof.

The present invention further provides a process for preparing compound(I), characterized in that the compound of the formula (VI) is used,this being prepared by the processes specified above, by converting thecompound of the formula (VI) to the compound of the formula (VII)

subsequently reacting the latter in an inert solvent in the presence ofa suitable base with the compound of the formula (VIIIa)

to give the compound of the formula (VIII)

and then reducing the latter in an inert solvent in the presence of asuitable reducing agent to give the compound (IX)

and thereafter reacting the latter with methyl chloroformate or withdimethyl dicarbonate in the presence of a suitable base with or withoutsolvent to give the compound of the formula (I), and optionallyconverting the resulting compounds of the formula (I) with theappropriate (i) solvents and/or (ii) acids or bases to the solvates,salts and/or solvates of the salts thereof.

The present invention further provides the compound of the formula (I)in crystalline form of polymorph I

characterized in that the x-ray diffractogram of the compound exhibitspeak maxima of the 2 theta angle at 5.9, 6.9, 22.7.

The present invention further provides the compound of the formula (I)in polymorph (I) as described above, characterized in that the x-raydiffractogram of the compound exhibits peak maxima of the 2 theta angleat 5.9, 6.9, 16.2, 16.5, 24.1, 22.7, 24.7.

The present invention further provides the compound of the formula (I)in crystalline form of polymorph I

characterized in that the IR spectrum of the compound exhibits bandmaxima at 1707, 1633, 1475 cm⁻¹.

The present invention further provides the compound of the formula (I)in polymorph (I) as described above, characterized in that the IRspectrum of the compound exhibits band maxima at 1707, 1633, 1566, 1475,1255, 1223 cm⁻¹.

The invention further provides a process for preparing the compound ofthe formula (I) in crystalline form of polymorph I, characterized inthat the compound of the formula (I), present in one or more polymorphsor as a solvate in an inert solvent, is stirred at a temperature of 20°C.-120° C. and the compound of the formula (I) is isolated incrystalline polymorph I.

Preferred solvents for the process for preparing the compound of theformula (I) in crystalline form of polymorph I are a mixture of ethylacetate/ethanol/water, isopropanol, a mixture of isopropanol/water,methanol, a mixture of methanol/water, acetonitrile, acetone,tetrahydrofuran and methyl tert-butyl ether.

A preferred temperature range for the process for preparing the compoundof the formula (I) in crystalline form of polymorph I is from 20° C. to90° C.

The present invention further provides a compound of the formula (I) inpolymorph (I) as described above for treatment of disorders.

The present invention further provides a medicament comprising acompound of the formula (I) in polymorph (I) as described above and nogreater proportions of any other form of the compound of the formula (I)in polymorph (I) as described above. The present invention furtherprovides a medicament comprising a compound of the formula (I) inpolymorph (I) as described above in more than 90 percent by weight basedon the total amount of the compound of the formula (I) present inpolymorph (I) as described above.

The present invention further provides for the use of the compound ofthe formula (I) in polymorph (I) as described above for production of amedicament for treatment of cardiovascular disorders.

The present invention further provides the method for treatment ofcardiovascular disorders by administering an effective amount of acompound of the formula (I) in polymorph (I) as described above.

The present invention further provides the compound of the formula (I)as the di-dimethyl sulphoxide solvate

characterized in that the x-ray diffractogram of the compound exhibitspeak maxima of the 2 theta angle at 18.8, 20.3, 21.7.

The present invention further provides the compound of the formula (I)as the di-dimethyl sulphoxide solvate, characterized in that the x-raydiffractogram of the compound exhibits peak maxima of the 2 theta angleat 12.0, 16.6, 17.8, 18.8, 20.3, 21.7.

The present invention further provides the compound of the formula (I)as the di-dimethyl sulphoxide solvate

characterized in that the IR spectrum of the compound exhibits bandmaxima at 1720, 1628, 1481 cm⁻¹.

The present invention further provides the compound of the formula (I)as the di-dimethyl sulphoxide solvate, characterized in that the IRspectrum of the compound exhibits band maxima at 1720, 1628, 1481, 1234,1041, 1017 cm⁻¹.

The present invention further provides a process for preparing thecompound of the formula (I) as the di-dimethyl sulphoxide solvate incrystalline form, characterized in that the compound of the formula (I),present in one or more polymorphs or as a solvate in dimethyl sulphoxideor a mixture of dimethyl sulphoxide and an inert solvent, for exampleethyl acetate, is stirred at a temperature of 20-120° C. and thedi-dimethyl sulphoxide solvate is isolated. Preference is given to atemperature range of 20 to 90° C.

The present invention further provides the compound of the formula (XIV)

and the salts, solvates and solvates of the salts thereof.

The present invention further provides the compound of the formula (XV)

and the salts, solvates and solvates of the salts thereof.

A. EXAMPLES

Abbreviations:

-   Ac acetyl-   CI chemical ionization (in MS)-   DCI direct chemical ionization (in MS)-   DMF dimethylformamide-   DMSO dimethyl sulphoxide-   eq. equivalent(s)-   ESI electrospray ionization (in MS)-   Et ethyl-   GC/MS gas chromatography-coupled mass spectrometry-   sat. saturated-   h hour(s)-   HPLC high-pressure high-performance liquid chromatography-   HV high vacuum-   conc. concentrated-   LC/MS liquid chromatography-coupled mass spectrometry-   Me methyl-   min minute(s)-   MS mass spectrometry-   NMR nuclear magnetic resonance spectroscopy-   rac racemic/racemate-   R_(f) retention factor (in thin layer chromatography on silica gel)-   RT room temperature-   R_(t) retention time (in HPLC)-   SFC supercritical fluid chromatography-   THF tetrahydrofuran-   UV ultraviolet spectrometry-   v/v volume to volume ratio (of a solution)    All X-Ray Diffractometry Data were Obtained with the Following    Acquisition Parameters:-   Diffractometer system PANalytical XPERT-PRO-   Scan axis Gonio-   Anode material Cu-   K-Alpha1 [Å] 1.54060-   K-Alpha2 [Å] 1.54443-   K-A2/K-A1 ratio 0.50000-   Scan Mode: Transmission-   Scan type: 2theta:omega-   2theta figure: ±0.2°    All Infrared Spectroscopy Data were Obtained with the Following    Acquisition Parameters:-   Spectrometer: Perkin Elmer Spectrum One with diamond ATR unit-   Parameter: 32 scans-   Resolution: 2 cm⁻¹

Example 1 2,2,3,3-Tetrafluoropropyl trifluoromethanesulphonate

Method A:

252.5 g (0.895 mol) of trifluoromethanesulphonic anhydride were heatedto 40° C. and, at this temperature, 130.0 g (0.984 mol) of2,2,3,3-tetrafluoro-1-propanol were metered in while cooling. After themetered addition had ended, the reaction mixture was heated to 70°-75°C. and stirred for 2 h. The mixture was cooled to 20° C. and thereaction solution was used without further purification in the reactionfor Example 2.

Method B:

50.0 g (0.379 mol) of 2,2,3,3-tetrafluoro-1-propanol were cooled to 0°C. and 106.8 g (0.379 mol) of trifluoromethanesulphonic anhydride wereadded dropwise at 0°-4° C. Subsequently, the reaction mixture wasstirred at 25° C. for 2 h, heated to 70°-75° C. and stirred for 2 h. Themixture was cooled to 20° C. and the reaction solution was distilled at116°-118° C. This gave 85.1 g (85.1% of theory) of the title compound.

¹H NMR (400 MHz, CDCl₃): δ=4.69 (t, J=11.86 Hz, 2 H) 5.54-6.23 (m, 1 H)ppm.

Example 2 4-(2,2,3,3-Tetrafluoropropyl)morpholine

Method A:

311.9 g (3.58 mol) of morpholine were dissolved in 290 ml ofdichloromethane and cooled to −15° C. At −15°-0° C., 371.4 g (max. 0.895mol) of the reaction solution from Example 1 were added dropwise whilecooling and then the mixture was stirred at 0°-5° C. for 30 min. Thereaction mixture was heated to 40° C. and stirred for 4.5 h. Aftercooling to 20° C., 320 ml of water were added and the phases wereseparated. The organic phase was washed three times with 190 ml eachtime of water and concentrated on a rotary evaporator at 30° C./30 mbar.The residue (160.7 g) was distilled at 67°-68° C./18 mbar. This gave151.7 g (84.3% of theory) of the title compound.

¹H NMR (400 MHz, CDCl₃): δ=2.53-2.70 (m, 4 H) 2.89 (tt, J=14.03, 1.74Hz, 2 H) 3.61-3.78 (m, 4 H) 5.83-6.22 (m, 1 H) ppm.

Method B:

158.5 g (1.82 mol) of morpholine were cooled to 5° C. At 5°-10° C.,189.5 g (max. 0.455 mol) of the reaction solution from Example 1 wereadded dropwise while cooling and then the mixture was stirred at 5°-10°C. for 30 min. The reaction mixture was heated to 40° C. and stirred for1 h. After cooling to 20° C., 160 ml of water and 160 ml of toluene wereadded and the phases were separated. The organic phase was washed with160 ml of water and concentrated on a rotary evaporator at 50° C./50mbar. The residue (81.0 g) was distilled at 67°-68° C./18 mbar. Thisgave 77.0 g (84.1% of theory) of the title compound.

Example 3 4-Methyl-4-(2,2,3,3-tetrafluoropropyl)morpholin-4-iummethanesulphonate

Method A:

143.7 g (1.31 mol) of methyl methanesulphonate were heated to 135° C.and, at this temperature, 250.0 g (1.243 mol) of the compound fromExample 2 were added dropwise. Subsequently, the mixture was stirred at100° C. for 22 h. The reaction mixture was cooled to 85° C. and 375 mlof isopropanol were added. After cooling to 0°-5° C., the mixture wasstirred for a further 30 min and the product was filtered off withsuction. The product was washed three times with 125 ml each time ofisopropanol and dried in a vacuum drying cabinet at 45° C. under agentle nitrogen stream. This gave 336.8 g (87.1% of theory) of the titlecompound.

¹H NMR (400 MHz, D₂O): δ=2.81 (s, 3 H) 3.55 (s, 3 H) 3.68-3.93 (m, 4 H)4.01-4.24 (m, 4 H) 4.33-4.51 (m, 2 H) 6.13-6.48 (m, 1 H) ppm.

Method B:

20.0 g (181.3 mmol) of methyl methanesulphonate were heated to 135° C.and, at this temperature, 35.1 g (172.7 mmol) of the compound fromExample 2 were added dropwise. The mixture was stirred at 135° C. for 3h and then 40 ml of water were added. After cooling to 50° C., theaqueous solution of the title compound was used in the subsequent stage(see Example 4).

Example 4 4-Methyl-4-[2,3,3-trifluoroprop-1-en-1-yl]morpholin-4-iummethanesulphonate

16.9 g (189.9 mmol) of 45% sodium hydroxide solution were metered intothe aqueous solution of the compound from Example 3, Method B (max.172.7 mmol) at 50°-55° C., and the mixture was stirred at 50° C. for 1h. The reaction mixture was cooled to 20° C. and the precipitated saltswere filtered off with suction and washed with 5 ml of water. Theaqueous product solution (102.1 g; max. 172.7 mmol) was used in thesubsequent stage (see Example 5).

For analytical purposes, a sample was concentrated and dried.

¹H NMR (400 MHz, D₂O): δ=2.81 (s, 3 H) 3.59 (s, 3 H) 3.76-3.85 (m, 2 H)3.97-4.09 (m, 4 H) 4.12-4.20 (m, 2 H) 6.39-6.69 (m, 1 H) 6.74-6.83 (m, 1H) ppm.

Example 5 2-Fluoro-3-(morpholin-4-yl)acrylaldehyde

Method A:

An aqueous solution of the compound from Example 4 (max. 251.5 mmol) washeated to 75° C. Subsequently, 43.8 g (503 mmol) of morpholine and 76.3g (755 mmol) of triethylamine were added dropwise. The mixture wasstirred at 75° C. for 2 h and cooled to 23° C., and 290 ml ofdichloromethane and 100 ml of triethylamine were added. The phases wereseparated, the aqueous phase was washed with a mixture of 290 ml ofdichloromethane and 100 ml of triethylamine, and the combined organicphases were filtered, washed with 250 ml of sat. aqueous potassiumcarbonate solution and concentrated on a rotary evaporator at 40° C. 50ml of toluene were added and the mixture was concentrated further. Thisgave 34.2 g (81.9% of theory) of the title compound.

Method B:

A mixture of 43.8 g (503 mmol) of morpholine and 76.3 g (755 mmol) oftriethylamine was heated to 75° C. and an aqueous solution of thecompound from Example 4 (max. 251.5 mmol) was added dropwise within 25min. Subsequently, the mixture was stirred at 75° C. for 2 h and cooledto 23° C., and 290 ml of dichloromethane and 100 ml of triethylaminewere added. The mixture was filtered, the phases were separated, theaqueous phase was washed with a mixture of 290 ml of dichloromethane and100 ml of triethylamine, and the combined organic phases were washedwith 250 ml of sat. aqueous potassium carbonate solution andconcentrated on a rotary evaporator at 40° C. 50 ml of toluene wereadded and the mixture was concentrated further. This gave 35.3 g (83.4%of theory) of the title compound.

¹H NMR (500 MHz, CDCl₃): δ=3.51-3.60 (m, 4 H) 3.72-3.83 (m, 4 H) 6.16(d, J=27.1 Hz, 1 H) 8.59 (d, J=18.9 Hz, 1 H) ppm.

Method C:

A mixture of 30.2 g (345.3 mmol) of morpholine and 52.5 g (518.0 mmol)of triethylamine was heated to 75° C. and the aqueous solution of thecompound from Example 4, Method B (max. 172.7 mmol) was added dropwiseat 75°-80° C. The mixture was stirred under reflux for 2 h, cooled to23° C. and washed with 100 ml of dichloromethane. The aqueous phase waswashed twice with a mixture of 100 ml of dichloromethane and 15 ml oftriethylamine, and the combined organic phases were washed with 85 ml ofsat. aqueous potassium carbonate solution and concentrated under reducedpressure at 45°-50° C. 120 ml of toluene and 60 ml of toluene weredistilled off. The suspension was stirred at room temperature overnight,and the product was filtered off with suction and dried in a vacuumdrying cabinet at 50° C. under a gentle nitrogen stream. This gave 19.2g (68.3% of theory) of the title compound.

Example 6 Ethyl5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate

Method A:

22.3 g (84.8 mmol) of ethyl5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate (preparationdescribed for Example 20A in WO 00/06569) were initially charged in 59.5ml of ethanol, and 11.0 ml (169.6 mmol) of methanesulphonic acid, 9.0 g(212.1 mmol) of lithium chloride and 15.0 g (84.8 mmol) of the compoundfrom Example 5 were added at RT. The mixture was stirred at refluxtemperature for 4.5 h. After cooling to room temperature, the productwas filtered off with suction, washed twice with 4.5 ml of ethanol andstirred with 325 ml of water for 1 h. The solids were filtered off withsuction, washed twice with 11.5 ml of water and dried in a vacuum dryingcabinet at 50° C. under a gentle nitrogen stream. This gave 21.8 g(81.0% of theory) of the title compound.

MS (ESIpos): m/z=318 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=1.37 (t, 3H), 4.40 (q, 2H), 5.86 (s, 2H),7.15-7.27 (m, 3H), 7.36-7.41 (m, 1H), 8.25 (d, 1H), 8.78 (s br., 1H)ppm.

Method B:

27.0 g (635.2 mmol) of lithium chloride and 42.2 g (254.1 mmol) of thecompound from Example 5 were initially charged in 75 ml of ethanol andheated to reflux temperature. At this temperature, a solution of 66.9 g(254.1 mmol) of ethyl5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate (preparationdescribed for Example 20A in WO 00/06569) and 33.0 ml (508.2 mmol) ofmethanesulphonic acid in 180 ml of ethanol were added within 10 min. Themixture was stirred at reflux temperature for 2 h, then 120 ml ofisopropanol were added, the mixture was cooled to 62° C., 0.6 g of thetitle compound were used for seeding and the mixture was cooled to 5° C.within 4 h. The product was filtered off with suction, stirred with 120ml of isopropanol, filtered off with suction, washed with 180 ml ofwater, stirred with 300 ml of water for 0.5 h, filtered off withsuction, washed with 300 ml of water and dried in a vacuum dryingcabinet at 50° C. under a gentle nitrogen stream. This gave 65.1 g(80.7% of theory) of the title compound.

Method C:

5.42 g (20.6 mmol) of ethyl5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate (preparationdescribed for Example 20A in WO 00/06569) were initially charged in 20ml of ethanol, and 1.5 g (41.1 mmol) of hydrogen chloride wereintroduced. This solution was metered into 3.42 g (20.6 mmol) of thecompound from Example 5 in 50 ml of ethanol at reflux temperature within10 min. The mixture was stirred at reflux temperature for 2 h, then 10ml of isopropanol were added and the mixture was cooled to 5° C. Theproduct was filtered off with suction, washed with 10 ml of isopropanoland dried in a vacuum drying cabinet at 50° C. under a gentle nitrogenstream. This gave 4.84 g (74.2% of theory) of the title compound.

Example 75-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

10 ml of ethanol, 14.9 ml (441.2 mmol) of formamide and 3.6 g (66.2mmol) of sodium methoxide solution in methanol (30%) were added to 7.0 g(22,1 mmol) of the compound obtained in Example 6. The reaction mixturewas heated to 95°-100° C. and the low boilers were distilled off. Themixture was stirred at 125° C. for 1.5 h, 30 ml of water were added, andthe mixture was cooled to room temperature and stirred for 1 h. Theprecipitated solids were filtered off with suction, washed three timeswith 8.5 ml each time of water and dried in a vacuum drying cabinet at45° C. under a gentle nitrogen stream. This gave 6.2 g (97.5% of theory)of the title compound.

MS (ESIpos): m/z=289 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=5.87 (s, 2H), 7.12-7.26 (m, 3H), 7.34-7.40(m, 1H), 7.60 (s br., 1H), 7.87 (s br., 1H), 8.28 (dd, 1H), 8.72 (dd,1H) ppm.

Example 85-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

17.3 g (60.0 mmol) of the compound obtained in Example 7 were heated to103°-107° C. in 40.5 ml of sulpholane and 5.4 ml of acetonitrile.Thereafter, 6.9 g (45.0 mmol) of phosphorus oxychloride were slowlyadded dropwise while stirring, the dropping funnel was rinsed with 2.8ml of acetonitrile, then the mixture was stirred at 107° C. for 1.5 huntil conversion was complete (HPLC). Thereafter, the mixture was cooledto room temperature, and 2.8 ml of sulpholane/acetonitrile (5:1 vol/vol)and then 17.8 ml of water were added dropwise. The mixture was stirredfor 0.5 h, a solution of 9.4 g of aqueous ammonia (28%) in 22.7 ml ofwater was added dropwise and the mixture was stirred for a further 2 h.The precipitated solids were filtered off with suction, washed threetimes with 20.5 ml each time of water and dried in a vacuum dryingcabinet at 50° C. under a gentle nitrogen stream. This gave 14.7 g(91.9% of theory) of the title compound.

MS (ESIpos): m/z=271 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=5.87 (s, 2H), 7.17-7.42 (m, 4H), 8.52 (dd,1H), 8.87 (dd, 1H) ppm.

Example 95-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamidehydrochloride

406.0 g (1.50 mol) of the compound from Example 8 were suspended in 2.08l of ethanol. Subsequently, 54.1 g (0.30 mol) of sodium methoxide inmethanol (30%) were added and the mixture was stirred at roomtemperature overnight. 88.4 g (1.65 mol) of ammonium chloride wereadded, and the mixture was heated to 65° C. and stirred at 65° C. for3.5 h. The solvents were distilled off and the residue was stirred with1.6 l of ethyl acetate overnight. The precipitated solids were filteredoff with suction, washed twice with 140 ml each time of ethyl acetateand dried in a vacuum drying cabinet at 50° C. under a gentle nitrogenstream. This gave 441.4 g (90.7% of theory) of the title compound.

MS (ESIpos): m/z=288 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=5.90 (s, 2H), 7.15-7.20 (m, 1H), 7.22-7.28(m, 1H), 7.29-7.35 (m, 1H), 7.36-7.43 (m, 1H), 8.48 (dd, 1H), 8.86 (dd,1H), 9.35 (br. s, 3H) ppm.

Example 10 [(E)-phenyldiazenyl]malononitrile

Method A:

262 g of conc. hydrochloric acid (2.59 mol) and 117.5 ml of water wereadded dropwise at 0°-5° C. to 1525 ml of water and 117.5 g (1.26 mol) ofaniline. Subsequently, a solution of 87.1 g (1.26 mol) of sodium nitritein 222.5 ml of water was added dropwise within 1 h and rinsed in with 60ml of water, and the mixture was stirred at 0°-5° C. for 15 min.Thereafter, at this temperature, a solution of 131.4 g (1.60 mol) ofsodium acetate in 665 ml of water (19 ml) was added dropwise within 45min and rinsed in with 60 ml of water, and a solution of 83.4 g (1.26mol) of malononitrile in 233 ml of ethanol was added dropwise within 1h. 68.5 ml of ethanol were used to rinse it in, and the mixture wasstirred at 0°-5° C. for 2 h. The yellow solids were filtered off withsuction and washed three times with 625 ml each time of water and with488 ml of cold toluene. The still-moist residue was dissolved in 872 gof DMF. This gave 1117.0 g of DMF solution of the title compound.

Method B:

87.4 g of conc. hydrochloric acid (0.86 mol) and 39.5 ml of water wereadded dropwise at 0°-5° C. to 508.5 ml of water and 39.2 g (0.42 mol) ofaniline Subsequently, a solution of 29.0 g (0.42 mol) of sodium nitritein 74.5 ml of water was added dropwise within 1 h and rinsed in with 20nil of water, and the mixture was stirred at 0°-5° C. for 15 min.Thereafter, at this temperature, a solution of 43.8 g (0.54 mol) ofsodium acetate in 221.5 ml of water was added dropwise within 45 min andrinsed in with 20 ml of water, and a solution of 27.8 g (0.42 mol) ofmalononitrile in 77.5 ml of ethanol was added dropwise within 1 h. 23 mlof ethanol were used to rinse it in, and the mixture was stirred at0°-5° C. for 2 h. The yellow solids were filtered off with suction andwashed three times with 208.5 ml each time of water and with 162.5 ml ofcold toluene. 103.1 g of moist product were obtained. 13.8 g of themoist product were dissolved in 13.9 g of sulpholane. This gave 27.7 gof sulpholane solution of the title compound.

Example 112-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-phenyldiazenyl]pyrimidine-4,6-diamine

Method A:

448.2 g (1.38 mol) of the compound from Example 9 were suspended in 1059ml of DMF. The mixture was heated to 85° C. and 212 ml (1.52 mol) oftriethylamine were added dropwise at this temperature. Subsequently,1751 g of the DMF solution from Example 10 were added dropwise within 20min and rinsed in with 490 ml of DMF, and the mixture was stirred at100° C. overnight. The reaction mixture was cooled to RT, 656 ml ofwater were added dropwise and the mixture was stirred at RT for 0.5 h,then cooled to 0°-5° C. and stirred for a further 1 h. The solids werefiltered off with suction, washed twice, each time with a solution of1443 g of water and 236 g of methanol, and then washed with 586 ml ofmethanol, suction-dried and dried in a vacuum drying cabinet at 50° C.under a gentle nitrogen stream. This gave 522.2 g (82.5% of theory) ofthe title compound.

¹H NMR (400 MHz, DMSO-d₆): δ=5.84 (s, 2 H) 7.14-7.28 (m, 3 H) 7.34-7.41(m, 2 H) 7.46-7.52 (m, 2 H) 7.95 (br. s, 2 H) 8.02 (dd, 2 H) 8.50 (br.s, 2 H) 8.70-8.73 (m, 1 H) 9.02-9.06 (m, 1 H) ppm.

Method B:

30.0 g (92.7 mmol) of the compound from Example 9 were suspended in 72ml of DMF. The mixture was heated to 100° C. and a mixture of 14.2 ml(101.9 mmol) of triethylamine and 150 g of the DMF solution from Example10 was added dropwise at this temperature within 30 min. 30 ml of DMFwere used to rinse it in and the mixture was stirred at 100° C. for 20h. The reaction mixture was cooled to 95°-90° C., 24 ml of water wereadded dropwise within 10 min, then the mixture was cooled to 0°-5° C.within 1.5 h and stirred for 1 h. The solids were filtered off withsuction, washed with a solution of 60 g of water and 60 g ofdimethylformamide, washed twice, each time with a solution of 50 g ofwater and 50 g of methanol, and then with 40 ml of methanol,suction-dried and dried in a vacuum drying cabinet at 50° C. under agentle nitrogen stream. This gave 35.5 g (83.7% of theory) of the titlecompound.

Method C:

11.7 g (36.0 mmol) of the compound from Example 9 were suspended in 15.6ml of sulpholane. The mixture was heated to 100° C. and a mixture of 5.5ml (39.6 mmol) of triethylamine and 27.7 g of the sulpholane solutionfrom Example 10 Method B was added dropwise at this temperature within35 min. 2 ml of sulpholane were used to rinse it in and the mixture wasstirred at 100° C. for 2.5 h. The reaction mixture was cooled to 60° C.,90 ml of isopropanol were added dropwise, then the mixture was cooled to0°-5° C. within 15 min and stirred for 2.5 h. The solids were filteredoff with suction, washed three times, each time with 50 g of water and24 ml of isopropanol, suction-dried and dried in a vacuum drying cabinetat 50° C. under a gentle nitrogen stream. This gave 14.2 g (85.9% oftheory) of the title compound.

Example 122-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5,6-triamine

Method A:

182.0 g (0.39 mol) of the compound from Example 11 were initiallycharged in 1.82 l of DMF and then 4.2 g of palladium (5% on carbon, 50%water-moist) were added. Hydrogenation was effected at 60° C. andhydrogen pressure 60 bar while stirring overnight. The mixture wasfiltered through kieselguhr and washed through with 150 ml of DMF andthen with 150 ml of methanol, and concentrated at 60°-70° C. down to aweight of 425 g of distillation residue. The residue was heated to75°-80° C., 300 ml of methanol were added dropwise at this temperatureand the mixture was stirred for 15 min. The mixture was cooled to RTwithin 1 h, then 1290 ml of water were added dropwise and the mixturewas stirred overnight. The solids were filtered off with suction, washedtwice with 500 ml each time of water, suction-dried and dried in avacuum drying cabinet at 50° C. under a gentle nitrogen stream. Thisgave 159.7 g of the title compound. The product has a content of 73.7%by weight and 12.4% by weight of DMF (80.3% of theory) and was used thusin the subsequent stage. According to the intensity of the water wash,the DMF content was in the range of 10-17% by weight.

Method B:

25.0 g of the DMF-containing solids from Method A were suspended in 220ml of water and filtered with suction through a suction filter. Thesolids were washed four times on the suction filter with 100 ml eachtime of water at 95° C., suction-dried and dried in a vacuum dryingcabinet at 50° C. under a gentle nitrogen stream. This gave 21.2 g ofthe DMF-free title compound.

MS (ESIpos): m/z=369 (M+H)⁺

For analytical purposes, a sample was purified by means of silica gelfiltration:

¹H NMR (400 MHz, DMSO-d₆): δ=4.04 (br. s, 2 H) 5.75 (s, 2 H) 5.86 (br.s, 4 H) 7.10-7.26 (m, 3 H) 7.32-7.39 (m, 1 H) 8.61-8.64 (m, 1 H) 8.85(dd, 1 H) ppm.

Example 13 Methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate

Method A:

4.0 g (77.0% by weight, 8.36 mmol) of the compound from Example 12 in37.9 ml of isopropanol were heated to 35° C. and then 0.84 ml (10.87mmol) of methyl chloroformate was added dropwise. The mixture wasstirred at 35°-40° C. for 20 h and heated to 50° C., and 9.5 ml ofmethanol were added. Subsequently, 1.9 ml of triethylamine were addeddropwise within 0.5 h and rinsed in with 1.3 ml of methanol, and themixture was stirred at 50° C. for 1 h. Thereafter, the reaction mixturewas cooled to RT and stirred at RT for 1 h, and the solids were filteredoff with suction, washed three times with 8 ml each time of ethanol,suction-dried and dried in a vacuum drying cabinet at 50° C. under agentle nitrogen stream. This gave 3.4 g of crude product. 3.0 g of thecrude product were stirred in 8 ml of DMSO for 5 min, 13.0 ml of ethylacetate and 50 mg of activated carbon were added, and the mixture washeated at reflux (84° C.) for 15 min. The suspension was hot-filteredand the filter residue was washed with 1.9 ml of ethyl acetate¹). 60 mlof ethyl acetate and 16 ml of ethanol were heated to 60° C., and thecombined filtrates were added dropwise and stirred at 60° C. for 1.5 h.The suspension was cooled to RT within 25 min, stirred for a further 1.5h, cooled further to 0°-5° C. and stirred for a further 1 h. The solidswere filtered off with suction, washed twice with 6.4 ml each time ofethyl acetate, suction-dried and dried in a vacuum drying cabinet at 50°C. under a gentle nitrogen stream. This gave 2.2 g (70.0% of theory) ofthe title compound.

MS (ESIpos): m/z=427 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.62 (br s, 3H), 5.79 (s, 2H), 6.22 (br s,4H), 7.10-7.19 (m, 2H), 7.19-7.26 (m, 1H), 7.32-7.40 (m, 1H), 7.67 and7.99 (2 br s, 1H), 8.66 (m, 1H), 8.89 (dd, 1H) ppm.

-   -   1) According to the preparation process described, the        di-dimethyl sulphoxide solvate is obtained at this point, and        this is characterized in Tables 2 and 4 by the reflections in        the x-ray diffractogram and bands in the IR spectrum.

The di-dimethyl sulphoxide solvate of the compound of the formula (I)has the advantage of much better filterability than the substance in theprior art. Furthermore, the preparation process via the di-dimethylsulphoxide solvate of the compound of the formula (I) leads to a veryhigh purity of the compound of the formula (I).

Method B:

4.0 g (10.8 mmol) of the compound from Example 12 Method B in 37.9 ml ofisopropanol were heated to 35° C. and then 1.1 ml (14.1 mmol) of methylchloroformate were added dropwise. The mixture was stirred at 35°-40° C.for 16.5 h and cooled to RT, and 2.1 ml of aqueous ammonia (28%) wereadded. Subsequently, 4.2 ml of water were added and the mixture wasstirred for 2.5 h. The solids were filtered off with suction, washedtwice with 5 ml each time of water, suction-dried and dried in a vacuumdrying cabinet at 50° C. under a gentle nitrogen stream. This gave 4.4 gof crude product.

Method C:

4.0 g (10.8 mmol) of the compound from Example 12 Method B in 37.9 ml ofisopropanol were heated to 35° C. and then 1.1 ml (14.1 mmol) of methylchloroformate were added dropwise. The mixture was stirred at 35°-40° C.for 16.5 h, and 9.5 ml of methanol were added at 50° C. Subsequently,2.42 ml of triethylamine were added dropwise within 20 min and rinsed inwith 1.3 ml of methanol, and the mixture was stirred at 50° C. for 1 h.Thereafter, the reaction mixture was cooled to RT and stirred at RT for1 h, and the solids were filtered off with suction, washed three timeswith 8 ml each time of methanol, suction-dried and dried in a vacuumdrying cabinet at 50° C. under a gentle nitrogen stream. This gave 4.3 gof crude product.

Method D:

6.9 g of the crude product were stirred in 18.4 ml of DMSO for 5 min,30.0 ml of ethyl acetate and 115 mg of activated carbon were added, andthe mixture was heated at reflux (84° C.) for 15 min. The suspension washot-filtered and the filter residue was washed with 4.4 ml of ethylacetate. 138 ml of ethyl acetate were heated to 50° C., and the combinedfiltrates were added dropwise and stirred at 45-50° C. for 1 h. Thesuspension was cooled to 0°-5° C. within 1.5 h and stirred for a further1 h. The solids were filtered off with suction, washed twice with 14.8ml each time of ethyl acetate and suction-dried for 1 h. 6.4 g of thedi-dimethyl sulphoxide solvate were obtained as a moist products).

Method E:

2.0 g of the di-dimethyl sulphoxide solvate were stirred at refluxtemperature in 40 ml of ethyl acetate and 11.1 ml of ethanol for 17 h,cooled to RT and stirred for a further 1 h. The solids were filtered offwith suction, washed four times with 1.4 ml each time of ethyl acetateand dried in a vacuum drying cabinet at 50° C. under a gentle nitrogenstream. This gave 1.4 g of the title compound present in polymorph I.

Method F:

0.5 g of the di-dimethyl sulphoxide solvate were stirred at refluxtemperature in 12.5 ml of solvent for 17 h, cooled to RT and stirred fora further 1 h. The solids were filtered off with suction, washed with 2ml of solvent and suction-dried for 30 min. This gave 0.3 g of the titlecompound present in polymorph I.

The following solvents were used:

-   1.) 9 ml of ethyl acetate/3.5 ml of ethanol/0.3 ml of water-   2.) 12.5 ml of isopropanol-   3.) 12.5 ml of isopropanol/0.3 ml of water-   4.) 12.5 ml of methanol-   5.) 12.5 ml of methanol/0.3 ml of water-   6.) 12.5 ml of acetonitrile-   7.) 12.5 ml of acetone-   8.) 12.5 ml of tetrahydrofuran,-   9.) 12.5 ml of methyl tert-butyl ether

Table 1 indicates the reflections of the x-ray diffractogram. Table 3shows the bands of the IR spectrum.

The compound (I) in crystalline polymorph I is notable for higherstability and more particularly for the fact that it is stable in themicronization process and hence no conversion and recrystallizationtakes place.

The compound of the formula (I) can be prepared by processes describedabove. This affords the compound of the formula (I) in a crystalpolymorph referred to hereinafter as polymorph I. Polymorph I has amelting point of 257° C. and a characteristic x-ray diffractogramfeaturing the reflections (2 theta) 5.9, 6.9, 16.2, 16.5, 24.1 and 24.7,and a characteristic IR spectrum featuring the band maxima (in cm⁻¹)1707, 1633, 1566, 1475, 1255 and 1223 (Tables 1 and 3, FIGS. 1 and 5).

Surprisingly, four further polymorphs, a monohydrate, a dihydrate, aDMF/water solvate and a di-dimethyl sulphoxide solvate, and also atriacetic acid solvate of the compound of the formula (I) were found.The compound of the formula (I) in polymorph II melts at approx. 253°C.; the compound of the formula (I) in polymorph III has a melting pointof approx. 127° C. Polymorph IV of the compound of the formula I meltsat a temperature of 246° C., while polymorph V has a melting point of234° C. The monohydrate contains approx. 4.1% water, the dihydratecontains 7.8% water, the DMF/water solvate contains 13.6%dimethylformamide and 0.9% water, the di-DMSO solvate contains 26.8%dimethyl sulphoxide and the triacetic acid solvate contains 29.7%acetate. Each of the crystalline forms mentioned has a characteristicx-ray diffractogram and IR spectrum (Tables 2 and 3, FIGS. 1-4, 6-14).

TABLE 1 X-ray diffractometry for polymorphs I to V Reflections PolymorphPolymorph Polymorph I Polymorph II III Polymorph IV V [2 theta] [2theta] [2 theta] [2 theta] [2 theta] 5.9 4.9 6.2 6.2 3.2 6.9 7.3 6.8 8.75.1 8.3 9.7 8.7 12.4 5.4 10.4 9.9 9.8 15.8 6.4 10.5 10.8 12.4 18.1 6.611.3 14.3 15.8 18.6 10.2 11.6 14.9 17.5 19.2 10.7 11.9 15.6 18.1 19.611.8 12.2 16.5 18.6 20.2 12.8 14.5 18.1 19.1 20.9 13.2 14.7 18.3 19.621.8 15.2 15.1 19.6 20.1 22.3 15.5 16.2 21.0 21.0 23.1 15.7 16.5 21.821.9 23.7 16.3 20.0 22.4 22.8 24.2 17.0 21.9 23.1 23.7 26.0 17.7 22.723.7 24.5 26.5 17.9 23.5 27.1 25.3 29.2 19.6 24.1 28.1 25.7 31.3 22.124.7 26.8 33.8 22.8 25.4 27.5 23.5 25.7 28.2 24.4 26.6 29.6 26.3 28.030.9 27.9 30.2 31.3 28.3 31.6 29.3 32.8 30.3 33.8 34.6

TABLE 2 X-ray diffractometry for polymorph hydrates and solvatesReflections DMF/water Acetic acid Monohydrate Dihydrate solvate di-DMSOsolvate solvate [2 theta] [2 theta] [2 theta] [2 theta] [2 theta] 6.05.9 8.2 6.9 5.3 8.5 7.9 9.2 11.0 7.2 9.6 8.7 9.7 12.0 9.3 12.1 9.0 11.913.8 10.0 13.6 11.8 12.5 14.1 10.7 15.5 13.7 12.7 15.7 11.0 17.3 14.713.3 16.1 11.6 18.2 15.8 14.1 16.2 11.9 19.3 16.4 15.6 16.6 12.5 19.718.1 16.0 17.1 14.1 20.2 19.3 16.5 17.7 14.4 20.9 19.8 16.8 17.8 14.821.5 20.6 17.6 18.8 16.6 22.2 21.7 18.3 19.9 18.0 23.5 21.7 19.3 20.318.8 24.1 22.5 19.4 20.7 19.2 25.7 22.7 19.6 21.3 19.4 26.8 22.9 19.821.7 19.6 27.5 23.4 20.0 21.9 19.7 29.4 23.7 20.5 22.4 20.1 30.8 24.920.6 22.8 20.4 32.2 25.5 20.7 23.6 21.0 26.0 21.0 24.1 21.6 26.8 21.824.4 22.9 27.1 22.2 25.2 23.5 27.8 22.4 25.5 24.1 28.9 22.8 25.9 24.430.7 23.1 26.6 24.8 31.3 23.6 26.9 25.5 32.0 23.9 28.9 26.5 24.8 29.926.8 25.2 30.9 27.7 25.6 33.2 31.5 25.8 33.4 26.1 33.9 26.7 26.8 27.227.6 28.1 28.4 28.6 29.4 29.7 30.3 30.6 31.4 31.5 31.7 32.1 32.4 32.632.7 34.1 34.3 34.7 35.6 35.9 36.6

TABLE 3 IR spectra of polymorphs I to V Band maxima Polymorph PolymorphPolymorph I Polymorph II III Polymorph IV V [cm⁻¹] [cm⁻¹] [cm⁻¹] [cm⁻¹][cm⁻¹] 690 691 697 698 691 744 752 744 752 745 761 771 753 773 759 774779 773 809 773 810 810 808 833 809 845 848 835 873 847 872 871 873 911873 899 903 913 936 896 960 933 935 955 912 1059 958 954 1058 933 10721031 1034 1077 961 1112 1067 1059 1104 1033 1157 1082 1075 1161 10571208 1111 1103 1207 1083 1223 1202 1161 1225 1112 1255 1223 1206 12371152 1305 1249 1256 1207 1319 1264 1237 1277 1224 1353 1305 1253 13171255 1370 1349 1278 1356 1305 1435 1368 1319 1370 1318 1475 1436 13551425 1351 1566 1456 1370 1457 1371 1620 1480 1424 1472 1436 1633 15661437 1490 1478 1707 1620 1458 1496 1567 2956 1704 1476 1573 1628 31302953 1489 1585 1707 3277 3132 1570 1618 2956 3332 3278 1587 1691 31433385 3361 1619 3208 3277 3490 3488 1695 3290 3319 3503 3203 3376 34523315 3482 3492 3379 3479

TABLE 4 IR spectra of the hydrates and solvates Band maxima DMF/waterAcetic acid Monohydrate Dihydrate solvate di-DMSO solvate solvate [cm⁻¹][cm⁻¹] [cm⁻¹] [cm⁻¹] [cm⁻¹] 696 745 662 713 709 743 752 724 762 739 761760 745 778 762 774 774 771 811 777 810 809 812 873 801 834 835 846 902835 873 874 867 953 872 912 913 896 1017 918 953 937 932 1041 941 1066955 965 1078 955 1079 1032 1054 1111 1059 1104 1061 1072 1164 1099 11601080 1096 1210 1113 1176 1105 1117 1234 1167 1205 1160 1160 1281 12361222 1174 1209 1321 1252 1236 1206 1243 1364 1357 1249 1224 1304 14321423 1278 1236 1356 1457 1456 1356 1259 1389 1481 1492 1370 1309 14341521 1577 1423 1356 1481 1569 1601 1456 1371 1561 1628 1643 1474 14221624 1720 1702 1491 1473 1654 3144 3342 1575 1497 1729 3288 1620 15753159 3423 1669 1622 3404 3294 1688 3498 3331 3195 3479 3304 3472 3676

FIGURES

FIG. 1: IR spectrum of the compound of the formula (I) in polymorphs I,II and III

FIG. 2: IR spectrum of the compound of the formula (I) in polymorphs IV,V and as the triacetic acid solvate

FIG. 3: IR spectrum of the compound of the formula (I) as the di-DMSOsolvate, DMF/water solvate and monohydrate

FIG. 4: IR spectrum of the compound of the formula (I) as the dihydrate

FIG. 5: X-ray diffractogram of the compound of the formula (I) inpolymorph I

FIG. 6: X-ray diffractogram of the compound of the formula (I) inpolymorph II

FIG. 7: X-ray diffractogram of the compound of the formula (I) inpolymorph III

FIG. 8: X-ray diffractogram of the compound of the formula (I) inpolymorph IV

FIG. 9: X-ray diffractogram of the compound of the formula (I) inpolymorph V

FIG. 10: X-ray diffractogram of the compound of the formula (I) as thetriacetic acid solvate

FIG. 11: X-ray diffractogram of the compound of the formula (I) as thedi-DMSO solvate

FIG. 12: X-ray diffractogram of the compound of the formula (I) as theDMF-water solvate

FIG. 13: X-ray diffractogram of the compound of the formula (I) as themonohydrate

FIG. 14: X-ray diffractogram of the compound of the formula (I) as thedihydrate

The invention claimed is:
 1. A process for preparing an aldehyde offormula (III)

in which R¹ and R² are each independently methyl, ethyl, isopropyl,phenyl or, together with the nitrogen atom to which they are bonded, are

comprising reacting trifluoromethanesulphonic anhydride with2,2,3,3-tetrafluoro-1-propanol, without solvent, and reacting theresulting 2,2,3,3-tetrafluoropropyl trifluoromethanesulphonate with acompound of formula (XIIa)

in which R¹ and R² are each as defined above to give a compound offormula (XIIIa)

in which R¹ and R² are each as defined above and reacting the compoundof formula (XIIIa) with methyl methanesulphonate to give a compound ofthe formula (XIVa)

in which R¹ and R² are each as defined above and reacting the compoundof (XIVa) with sodium hydroxide to give a compound of formula (XVa)

in which R¹ and R² are each as defined above and reacting the compoundof formula (XVa) with a compound of the formula (XIIa) to give thecompound of formula (III).